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PubMed2006

Managing patients with low-risk MDS.

Supportive care with blood transfusion and administration of hematopoietic growth factors (eg, erythropoietin, colony-stimulating factors) has been the standard of care for patients with low-risk myelodysplastic syndromes (MDS), a group of disorders characterized by hyperproliferation of the bone marrow and ineffective hematopoiesis. However, the development of new drugs, including lenalidomide, azacitidine, and decitabine, has led to a new era of more effective treatment for MDS. Further, the use of classification and risk stratification has allowed for the identification of individuals who are expected to benefit from some therapies while simultaneously excluding over-treatment and unnecessary toxicity in those who are unlikely to benefit from specific drugs. In this Clinical Roundtable Monograph, the faculty discusses the epidemiology, classification, and risk stratification for MDS, medical and nursing issues associated with supportive care and the new therapies for low-risk MDS, and patient education and other strategies for the optimization of quality of life in patients with low-risk MDS.

Antimetabolites, Antineoplastic↗
PubMed2006

Chronic lymphocytic leukemia: current and emerging treatment approaches.

In the last decade, advances in the treatment of patients with chronic lymphocytic leukemia (CLL) have improved responses and survival outcomes dramatically. Chlorambucil had been the cornerstone of treatment for decades. Now, treatment approaches typically include a purine nucleoside analog, such as fludarabine, in combination with immunotherapy, most commonly rituximab but also alemtuzumab. Several clinical trials of patients with untreated CLL have reported overall response rates as high as 95% with chemoimmunotherapy. Combinations include fludarabine, cyclophosphamide, and rituximab (FCR); pentostatin, cyclophosphamide, and rituximab; fludarabine and rituximab; and fludarabine and alemtuzumab. FCR has demonstrated complete response rates of 70% as frontline therapy. In addition, molecular prognostic indicators, such as IgVH mutational status, ZAP-70 expression, and chromosomal mutations (trisomy 12; 17p, and 11q deletions) are proving useful in identifying patients with poor-risk disease. Furthermore, advanced technologies such as polymerase chain reaction and flow cytometry can be used to detect minimal residual disease with increasing sensitivity. Elimination of minimal residual disease has been linked to improved survival and become an important clinical goal. While overall response rates with current chemotherapy treatments are superior to those seen with single agents (eg, chlorambucil), many CLL patients still fall short of achieving a complete response. Novel agents with unique, nonoverlapping mechanisms of action (eg, oblimersen sodium, lenalidomide, HuMax-CD20, GX15-070), and other treatments are under investigation in an attempt to further improve outcomes.

Alemtuzumab↗
PubMed2003

Moving disease biology from the lab to the clinic.

Multiple myeloma (MM) cells home to and adhere to extracellular matrix proteins and to bone marrow stromal cells (BMSCs); and in the BM microenvironment, grow, survive, resist drugs, and migrate under the influence of cytokines including interleukin-6, vascular endothelial growth factor, tumor necrosis factor alpha, and insulin-like growth factor (IGF)-1. Proliferation is via the Ras/Raf MAPK cascade, drug resistance via PI3-K/Akt signaling, and migration via PKC dependent pathways. Novel therapies that target not only the MM cell, but also the BM microenvironment, can overcome drug resistance in vitro and in vivo in murine human MM models. For example, immunomodulatory derivatives of thalidomide (IMiDs) and the proteasome inhibitor PS-341 both induce apoptosis of MM cell lines and patient cells refractory to melphalan, doxorubicin, and dexamethasone; abrogate MM cell binding to fibronectin and BMSCs and related protection against immune- and drug-induced apoptosis; block production of cytokines which promote MM cell growth, survival, drug resistance, and migration; inhibit angiogenesis; and stimulate host anti-tumor immunity. In the setting of relapsed refractory MM, a Phase I trial of the IMiD CC5013 shows stable paraprotein or better in 20 of 24 (79%) patients, with a favorable toxicity profile. In this same patient population 85% of 54 patients treated in a Phase II trial of PS-341 achieved either paraprotein response (50%) or stable disease (35%). Cellular and gene microarray studies comparing PS-341 and an IkappaB kinase inhibitor, PS-1145, suggest that selective NF-kappaB blockade cannot account for all the anti-MM activity of PS-341. Finally, cellular and signaling studies provide the preclinical rationale for combining these novel agents with conventional therapies, or with each other, to enhance efficacy. These novel therapeutics therefore represent a new treatment paradigm in MM targeting the tumor cell in its microenvironment to overcome classical drug resistance and improve patient outcome. Future studies should define the utility of these agents as primary therapy, treatment for first relapse, and maintenance therapy.

Bone Marrow↗
PubMed2003

Novel therapies in multiple myeloma.

The discovery of the activity of thalidomide in myeloma in the late 1990s transformed the therapy of myeloma dramatically. Apart from providing a useful treatment option for patients with myeloma, it has spurred clinical investigation of several other nonchemotherapeutic agents for this disease. These active, promising agents include CC-5013 (a thalidomide analog) and bortezomib (a proteasome inhibitor), as well as other agents, such as arsenic trioxide, ENMD 0995 and 2-methoxyestradiol. Preliminary data show that a number of these agents are active in treating disease that has relapsed after conventional chemotherapy as well as after high-dose therapy and transplantation, and some agents are active even after other novel agents have failed. The only novel drug that is commercially available currently is thalidomide, which has a therapeutically relevant benefit at all stages of the disease. A therapeutic trial of thalidomide is essential for all patients with myeloma. There are in vitro and in vivo data showing synergy between some of the novel agents. Although these novel drugs are typically used for treating disease that is refractory to or has relapsed after cytotoxic therapy, it is likely that they will start being used as part of frontline therapy, either by themselves or in combination with chemotherapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2005

Promising systemic therapy for renal cell carcinoma.

In the United States, advanced kidney cancer accounts for over 12,000 deaths each year. Immunotherapy with either interferon or interleukin-2 (IL-2) has been the standard of care for over two decades. High-dose IL-2 can apparently cure 10% to 15% of patients treated, but due to the required inpatient care and the attendant toxicities, it is only administered to less than 1,000 patients per year in the United States (Chiron, personal communication). Interferon is a less active agent than IL-2 but it has still been shown to be superior to therapy with either megesterol or vinblastine. Interferon typically results in very few long-term responses and is given to most patients with metastatic kidney cancer. Median survival after interferon therapy is dependent on risk group but is typically 12 to 15 months. Thus, new therapies are urgently needed in this refractory disease. Novel compounds currently being tested in clinical trials are showing promise in advanced kidney cancer. The molecular targets of these drugs include interfering with the vascular endothelial growth factor receptors or the raf kinase pathway, angiogenesis inhibition, and antimicrotubule agents. A review of the preclinical and early clinical development of some of these novel compounds will be discussed.

Animals↗
PubMed2004

Immunomodulatory drugs inhibit expression of cyclooxygenase-2 from TNF-alpha, IL-1beta, and LPS-stimulated human PBMC in a partially IL-10-dependent manner.

Immunomodulatory drugs (IMiDs) are potent inhibitors of TNF-alpha and IL-1beta and elevators of IL-10 production in LPS-stimulated human PBMC. They are currently in clinical trials for various diseases, including multiple myeloma, myelodysplastic syndrome, and melanoma. In the present study, we have investigated the effects of thalidomide, CC-5013 and CC-4047 on the expression of COX-2 by stimulated PBMC. Our results show that thalidomide and IMiDs inhibited the expression of COX-2 but not the COX-1 protein in LPS-TNF-alpha and IL-1beta stimulated PBMC and shortened the half-life of COX-2 mRNA in a dose-dependent manner. They also inhibited the synthesis of prostaglandin E2 from LPS-stimulated PBMC. While anti-TNF-alpha or IL-1beta neutralizing antibodies had no effect on COX-2 expression, anti-IL-10 neutralizing antibody elevated the expression of COX-2 mRNA, and protein from treated PBMC. These data suggest that the anti-inflammatory and anti-tumor effects of IMiDs may be due in part to elevation of IL-10 production and its subsequent inhibition of COX-2 expression.

Blotting, Northern↗
PubMed2004

Determination of CC-5013, an analogue of thalidomide, in human plasma by liquid chromatography-mass spectrometry.

A high-performance liquid chromatographic assay with MS detection has been developed for the quantitative determination of the anti-angiogenic agent CC-5013 in human plasma. Sample pretreatment involved liquid-liquid extraction with acetonitrile/1-chlorobutane (4:1, v/v) solution containing the internal standard, umbelliferone. Separation of the compounds of interest was achieved on a column packed with Waters C18 Nova-Pak material (4 microm particle size; 300 mm x 3.9 mm internal diameter) using acetonitrile, de-ionized water, and glacial acetic acid in ratios of 20:80:0.1 (v/v/v) (pH 3.5) delivered at an isocratic flow rate of 1.00 ml/min. Simultaneous MS detection was performed at m/z 260.3 (CC-5013) and m/z 163.1 (umbelliferone). The calibration curve was fit to a linear response-concentration data over a range of 5-1000 ng/ml using a weighting factor of 1/x. Values for accuracy and precision, obtained from four quality controls analyzed on three different days in replicates of five, ranged from 98 to 106% and from 5.5 to 15.5%, respectively. The method was successfully applied to study the pharmacokinetics of CC-5013 in a cancer patient receiving the drug as single daily dose.

Calibration↗
PubMed2005

[Thalidomide: mechanisms of action and new insights in hematology].

Purpose. - Thalidomide, a major teratogen drug, was rehabilitated mainly in malignant hemopathy. Current knowledge and key points. - Thalidomide-mechanisms of action are well known, multiple, they combine immunomodulatory, antiangiogenic properties, and the modulation of cytokines, particularly tumour necrosis factor-alpha. Multiple trials are ongoing, however, the main indication remain multiple myeloma with a response rate of 30% in relapsed patients. Future prospects and projects. - New structural analogues of the thalidomide which priviligiate some of the thalidomide-specific mechanisms of action, the selected cytokine inhibitory drugs (SelCIDS) and the immunomodulatory drugs (IMiDs) family are under evaluation. The IMiDs, which mechanism is based on stimulation of T lymphopoiesis rather than inhibition of tumour necrosis factor-alpha, are under clinical trials in multiple myeloma with interesting results.

Amyloidosis↗
PubMed2006

Immunomodulating drugs for chronic lymphocytic leukaemia.

Chronic lymphocytic leukaemia (CLL) is a malignant haematological disorder that remains mostly incurable; more than 95% of patients have disease of B-cell origin. Advances with targeted agents such as monoclonal antibodies, antisense therapy, or both these techniques combined with traditional chemotherapy have improved the frequency of remission. The clinical course of CLL is marked by frequent relapse, and there are limited therapeutic options for patients with relapsed or refractory disease. The morphologically mature CLL clone regulates the microenvironment through modulation of the cytokine milieu that aids its growth and survival, and has a role in immune escape. Targeting of the tumour-cell microenvironment has not been investigated as a treatment option for CLL. Immunomodulating agents are a new class of drugs that change expression of various cytokines and that costimulate immune effector cells.

Aged↗
PubMed2004

Phase I study to determine the safety, tolerability and immunostimulatory activity of thalidomide analogue CC-5013 in patients with metastatic malignant melanoma and other advanced cancers.

We assessed the safety, tolerability and efficacy of the immunomodulatory drug, CC-5013 (REVIMID trade mark ), in the treatment of patients with metastatic malignant melanoma and other advanced cancers. A total of 20 heavily pretreated patients received a dose-escalating regimen of oral CC-5013. Maximal tolerated dose, toxicity and clinical responses were evaluated and analysis of peripheral T-cell surface markers and serum for cytokines and proangiogenic factors were performed. CC-5013 was well tolerated. In all, 87% of adverse effects were classified as grade 1 or grade 2 according to Common Toxicity Criteria and there were no serious adverse events attributable to CC-5013 treatment. Six patients failed to complete the study, three because of disease progression, two withdrew consent and one was entered inappropriately and withdrawn from the study. The remaining 14 patients completed treatment without dose reduction, with one patient achieving partial remission. Evidence of T-cell activation was indicated by significantly increased serum levels of sIL-2 receptor, granulocyte-macrophage colony-stimulating factor, interleukin-12 (IL-12), tumour necrosis factor-alpha and IL-8 in nine patients from whom serum was available. However, levels of proangiogenic factors vascular endothelial growth factor and basic foetal growth factor were not consistently affected. This study demonstrates the safety, tolerability and suggests the clinical activity of CC-5013 in the treatment of refractory malignant melanoma. Furthermore, this is the first report demonstrating T-cell stimulatory activity of this class of compound in patients with advanced cancer.

Adolescent↗
PubMed2002

Thalidomide and its analogues have distinct and opposing effects on TNF-alpha and TNFR2 during co-stimulation of both CD4(+) and CD8(+) T cells.

Thalidomide (Thd) is clinically useful in a number of conditions where its efficacy is probably related to its anti-TNF-alpha activity. More recently, Thd has also been shown to co-stimulate T cells and second generation co-stimulatory (IMiD trade mark ) analogues are currently being assessed in the treatment of cancer patients. However, in contrast to their known suppressive effects during inflammatory stimuli, the effects of Thd/IMiDs on TNF-alpha and TNF receptors (TNFRs) during T cell co-stimulation are not known. We sought to determine the effect of Thd, two clinically relevant IMiDs (CC-4047, ACTIMID trade mark and CC-5013, REVIMID trade mark ) and a non-stimulatory SelCID analogue (CC-3052) on TNF-alpha production and on the expression and shedding of TNFRs during co-stimulation. We found that co-stimulation of PBMC with Thd/IMiDs, but not CC-3052, prevented alphaCD3-induced T cell surface expression of TNFR2 and thereby reduced soluble TNFR2 (sTNFR2) levels. However, there was no effect on total (surface/intracellular) TNFR2 protein expression, suggesting inhibition of trafficking to the cell membrane. The extent of co-stimulation by Thd/IMiDs (assessed by CD69/CD25 expression and IL-2/sIL-2Ralpha production) was similar for CD4+ and CD8+ T lymphocytes and correlated with TNFR2 inhibition. Co-stimulation, but not the early inhibitory effect on TNFR2, was IL-2-dependent and led to increased TNF-alpha production by both CD4+ and CD8+ T lymphocytes. The clinical relevance of this observation was confirmed by the elevation of serum TNF-alpha during REVIMID trade mark treatment of patients with advanced cancer. Together, these results suggest a possible role for TNF-mediated events during co-stimulation and contrast with the TNF inhibitory effects of Thd and its analogues during inflammatory stimuli.

Adjuvants, Immunologic↗
PubMed2003

Thalidomide and CC-5013 in multiple myeloma: the University of Arkansas experience.

Based on the activity of single-agent thalidomide in relapsed/refractory multiple myeloma in a landmark phase II study of 169 patients conducted at the University of Arkansas for Medical Sciences (UAMS), UAMS initiated several trials of thalidomide and the more potent thalidomide analog CC-5013. In an ongoing trial evaluating thalidomide plus the proteasome inhibitor bortezomib and dexamethasone in patients with relapsed/refractory disease following stem cell transplantation, approximately 50% of patients have experienced a paraprotein reduction of 50% or greater. In patients without cytogenetic abnormalities, the estimated 12-month event-free and overall survival rates are 69% and 100%, respectively. In a second ongoing trial building on the UAMS Total Therapy I regimen, newly diagnosed patients are randomized to thalidomide or no thalidomide pretransplantation followed by consolidation therapy with dexamethasone and multiagent chemotherapy post-transplantation (Total Therapy II). Although the Total Therapy II regimen appears to be superior to the original Total Therapy I regimen, assessment of the effect of thalidomide on Total Therapy II is pending accrual completion. Lastly, based on the increased potency and reduced toxicity profile of CC-5013 compared with thalidomide, a study of CC-5013 in patients with relapsed/refractory disease following transplantation was initiated. Patients are randomized to CC-5013 25 mg daily for 20 days versus CC-5013 50 mg every other day for 10 days. Preliminary results indicate the superiority of the 25-mg arm, with 40% of patients randomized to that arm experiencing a paraprotein reduction of 50% or greater. These preliminary results corroborate the role for thalidomide and CC-5013 in relapsed/refractory and newly diagnosed multiple myeloma based on the UAMS phase II study as well as several other studies of these agents outside of UAMS.

Adjuvants, Immunologic↗
PubMed2003

The role of immunomodulatory drugs in multiple myeloma.

Thalidomide has shown promise in the treatment of newly diagnosed multiple myeloma and relapsed/refractory disease, but side effects such as somnolence, constipation, and neuropathy limit its use. CC-5013, an immunomodulatory drug (IMiD), is more potent than thalidomide. CC-5013 has various immunomodulatory effects, including growth arrest or apoptosis of drug-resistant myeloma cell lines and inhibition of binding of myeloma cells to bone marrow stromal cells. Clinically, 17 of 24 patients (71%) with relapsed/refractory disease experienced a reduction of paraprotein of > or = 25% following treatment with CC-5013, including 11 who had a history of treatment with thalidomide. Another two experienced stable disease. Median time to best response was 2 months (range, 1 to 11) and median duration was 6 months (range, 2 to 18). Grade 3 thrombocytopenia was seen in 20% of patients; grade 3 neutropenia was seen in 60%; and grade 4 neutropenia was seen in 16%. CC-5013 use was not associated with somnolence, constipation, or neuropathy. This article reviews thalidomide in multiple myeloma, the effects of thalidomide analogues IMiDs, and the preclinical and clinical data on CC-5013 in relapsed/refractory multiple myeloma.

Adjuvants, Immunologic↗
PubMed2004

Clinical update: novel targets in multiple myeloma.

Novel therapies that can target the multiple myeloma (MM) cell, the MM cell-patient bone marrow interaction, and the bone marrow milieu can overcome resistance to conventional therapy in preclinical models and clinical trials. Both proteasome inhibitor bortezomib and immunomodulatory drug Revimid (Celgene Corporation, Warren, NJ) have gone from laboratory bench to bedside in 3 to 4 years, and achieve responses even in patients with relapsed refractory MM. They are now undergoing clinical evaluation, alone and combined with conventional and novel therapies, for treatment of patients earlier in their disease course, and offer great promise to improve patient outcome in MM.

Animals↗
PubMed2002

High-dose therapy and immunomodulatory drugs in multiple myeloma.

The principle of alkylating agent dose intensity, especially with melphalan-based tandem autotransplants, has been effective in increasing the rate of complete remission beyond 40% and effecting 10-year survivorship in about 40% of the three fourths of patients presenting without cytogenetic abnormalities (Total Therapy I). Further dose escalation and post-transplant consolidation therapy, as practiced with Total Therapy II, seems to further improve results in these patients, but not in those with chromosome 13 abnormalities or lactate dehydrogenase elevation. Phase III trials for post-transplant relapse indicate higher complete remission and near-complete remission rates among patients randomized to thalidomide added to dexamethasone versus dexamethasone alone. In a phase I/II study, thalidomide derivative CC-5013, with less sedative and neurotoxic effects, promoted responses in eight of 15 patients with post-transplant relapse, refractory to other salvage therapies, at dose levels of > or = 25 mg daily. Based on a profound graft-vs-myeloma effect with allografts, mini-allotransplants were evaluated in 31 high-risk patients with cytogenetic abnormalities and prior autotransplants; all nine with responsive disease and only one prior autotransplant remain disease-free and alive. Such mini-allotransplants are now offered as consolidation after one standard autotransplant to patients with cytogenetic abnormalities. The systematic application of gene expression profiling attempts to classify multiple myeloma (MM) patients according to molecular features and to dissect the genetic basis for drug sensitivity or resistance. Given the availability of an expanding treatment armamentarium (eg, thalidomide, CC-5013, the proteasome inhibitor PS-341, farnesyltransferase inhibitors, IL-6 receptor antibody, endothelial receptor inhibitor), gene expression profiling is anticipated to help in the selection of agents with the greatest probability of activity toward individualized treatment. Careful scrutiny of gene expression will also help in the identification of unrecognized targets for therapeutic intervention.

Antineoplastic Combined Chemotherapy Protocols↗